DE3530147A1 - USE OF DIAZAPHOSPHORINES TO CONTROL ENDOPARASITES - Google Patents

Description

The present invention relates to the use of Diazaphosphorins for the control of endoparasites in the Veterinary medicine.

The use of diazaphosphorines for pest control in plants and to control ectoparasites in animals has already become known (CH-PS 5 43 563). However, there is nothing about their suitability for the control of endoparasites, in particular of Helminthen, became known.

It has been found that diazaphosphorines of the formula I in which
R ^{1 represents} aryloxy or arylthio,
R ^{2 represents} hydrogen, alkyl, aryl or aralkyl,
R ^{3 represents} hydrogen, alkyl, aryl or aralkyl,
R ^{4 represents} the rest of the formula, in which
X ^{1 represents} O or S,
R ^{5 represents} hydrogen or alkyl,
R ^{6 represents} optionally substituted phenyl,
are ideal for combating endoparasites in veterinary medicine.

The compounds of formula I can be in the form of their various Tautomers (keto / enol) and as mixtures of these tautomers, and in the form of their salts with bases are available.

The compounds of formula I are known or have not produce themselves analogously to known processes.

The compounds of formula I are obtained by z. B. diazaphosphorines of formula II in which
R ¹ , R ² , R ^{3 have} the meaning given above,
with isocyanates of the formula III

in which
R ^{6 has} the meaning given above
if appropriate in the presence of catalysts,
or by
Diazaphosphorins of formula IV in which
R ¹ , R ² , R ^{3 have} the meaning given above,
R ^{7 represents} C _1-4 alkyl
with amines of formula V

in which
R ⁵ and R ^{6 have} the meaning given above
implements.

Compounds of the formula I in which are preferred
R ^{1 represents} phenoxy or phenylthio, in particular phenoxy, which can be substituted one or more times, identically or differently, by the following substituents: alkyl having preferably 1 to 4, in particular 1 or 2, carbon atoms, such as methyl, ethyl, n- and i-propyl and n-, i- and t-butyl; Alkoxy preferably having 1 to 4, in particular 1 or 2, carbon atoms, such as methoxy, ethoxy, n- and i-propyloxy and n-, i- and t-butyloxy; Alkylthio with preferably 1 to 4, in particular 1 or 2 carbon atoms, such as methylthio, ethylthio, n- and i-propylthio and n-, i- and t-butylthio; Haloalkyl with preferably 1 to 4, in particular 1 or 2 carbon atoms and preferably 1 to 5, in particular 1 to 3 halogen atoms, where the halogen atoms are identical or different and are halogen atoms, preferably fluorine, chlorine or bromine, in particular fluorine, such as trifluoromethyl or fluorine - or chloroethyl; Haloalkoxy with preferably 1 to 4 in particular 1 or 2 carbon atoms and preferably 1 to 5 in particular 1 to 3 halogen atoms, where the halogen atoms are identical or different and are preferably fluorine, chlorine, bromine, in particular fluorine, such as trifluoromethoxy; Haloalkylthio with preferably 1 to 4 in particular 1 or 2 carbon atoms and preferably 1 to 5 in particular 1 to 3 halogen atoms, the halogen atoms being identical or different and preferably being fluorine, chlorine, bromine, in particular fluorine, such as trifluoromethylthio; Alkylenedioxy with preferably 1 or 2 carbon atoms such as methylenedioxy or ethylenedioxy; halogen-substituted alkylenedioxy with preferably 1 or 2 carbon atoms and preferably 1 to 4, in particular 2 to 3 halogen atoms, the halogen atoms being the same or different and preferably being fluorine or chlorine, in particular fluorine, such as difluoromethylene dioxy, trifluoroethylene dioxy, tetrafluoroethylene dioxy; Hydroxy; Halogen, preferably fluorine, chlorine, bromine and iodine, especially chlorine and bromine; Cyano; Nitro; Amino; Monoalkyl- and dialkylamino with preferably 1 to 4, in particular 1 or 2 carbon atoms per alkyl group, such as methylamino, methyl-ethyl-amino, n- and i-propylamino and methyl-n-butylamino; Formyl, carboxyl; Alkylcarbonyl preferably having 2-4 carbon atoms; Carbalkoxy preferably having 2 to 4, in particular 2 or 3, carbon atoms, such as carbomethoxy and carboethoxy; Sulfo (-SO ₃ H); Alkylsulfonyl preferably having 1 to 4, in particular 1 or 2, carbon atoms, such as methylsulfonyl and ethylsulfonyl; Arylsulfonyl preferably having 6 or 10 aryl carbon atoms, such as phenylsulfonyl; Phenyl, naphthyl, phenoxy, naphthoxy, phenylthio, naphthylthio which in turn can be substituted.
R ^{2 represents} hydrogen, C ₁ -C ₄ -alkyl, phenyl, benzyl which may optionally be substituted,
R ^{3 represents} hydrogen, C ₁ -C ₄ alkyl, phenyl, benzyl which may be optionally substituted,
X ^{2 represents} O,
R ^{5 represents} hydrogen or C _1-4 alkyl,
R ^{6 represents} phenyl which optionally carries one or more of the following substituents: alkyl having preferably 1 to 4, in particular 1 or 2, carbon atoms, such as methyl, ethyl, n- and i-propyl and n-, i- and t-butyl ; Haloalkyl preferably having 1 to 4, in particular 1 or 2, carbon atoms and preferably 1 to 5, in particular 1 to 3, halogen atoms, the halogen atoms being identical or different and being halogen atoms, preferably fluorine, chlorine or bromine, in particular fluorine, such as trifluoromethyl; Hydroxy; Halogen, preferably fluorine, chlorine, bromine and iodine, especially chlorine and bromine; Cyano; Nitro; Amino; Monoalkyl- and dialkylamino with preferably 1 to 4, in particular 1 or 2 carbon atoms per alkyl group, such as methylamino, methylethylamino, n- and i-propylamino and methyl-n- butylamino; Formyl; Carboxyl; Alkylcarbonyl preferably having 2-4 carbon atoms; Carbalkoxy preferably having 2 to 4, in particular 2 or 3, carbon atoms, such as carbomethoxy and carboethoxy; Sulfo (-SO ₃ H); Arylsulfonyl preferably having 6 or 10 aryl carbon atoms, such as phenylsulfonyl; Phenyl, naphthyl, which in turn can be substituted.

Compounds of the formula I are particularly preferred
in which
R ^{1 represents} phenoxy which optionally carries one or more of the following substituents:
Halogen in particular fluorine, chlorine, bromine, NO ₂ , C ₁ -C ₄ -alkoxy in particular methoxy, ethoxy, C ₁ -C ₄ -alkyl in particular methyl, ethyl, propyl, C ₁ -C ₄ -alkylthio in particular methylthio, ethylthio, C ₁ -C ₄ -haloalkyl, in particular trifluoromethyl, C ₁ -C ₄ - halogenoalkoxy, in particular trifluoromethoxy, C ₁ -C ₄ - haloalkylthio particular trifluoromethylthio. The substituents are preferably in the 3- and 4-position of the phenyl ring.
R ^{2 represents} C ₁ -C ₄ alkyl, phenyl, benzyl,
R ^{3 represents} C ₁ -C ₄ alkyl, phenyl, benzyl,
X ^{1 represents} O,
R ^{5 represents} hydrogen,
R ^{6 represents} phenyl which is optionally substituted by nitro, halogen, in particular fluorine, chlorine, bromine, C ₁ -C ₄ -alkyl in particular methyl or ethyl, C ₁ -C ₄ -haloalkyl, in particular trifluoromethyl.

Compounds of the formula I in which are very particularly preferred
R ^{1 represents} phenoxy, which is optionally substituted in the 3 or 4 position by halogen, in particular chlorine, NO ₂ , C ₁ -C ₄ -alkyl, in particular methyl, C ₁ -C ₄ -alkoxy, in particular methoxy,
R ^{2 represents} C ₁ -C ₄ alkyl, in particular methyl or ethyl, phenyl,
R ^{3 represents} C ₁ -C ₄ alkyl, in particular methyl, ethyl, propyl, benzyl,
X ^{2 represents} O,
R ^{5 represents} hydrogen,
R ^{6 represents} phenyl, optionally substituted by NO ₂ , chlorine or methyl.

The following compounds of the formula I may be mentioned in particular:

As bases with which the compounds of formula I salts The following may be mentioned: alkali and alkaline earth hydroxides, Ammonia, primary, secondary and tertiary Amines. The following bases are particularly preferred: Triethylamine, isopropylamine, t-butylamine, pyridine, α-picoline, trimethylamine, diisopropylamine, morpholine, Pyrrolidine, hexamethyleneimine.  

The active compounds according to the invention are broadly effective against Endoparasites. They act primarily against trematodes and Nematodes, especially liver fluke and gastric and intestinal nematodes the ruminant. They also work against those gastric and intestinal nematodes that against the common and resistant to benzimidazole anthelmintics so that they can no longer be adequately treated.

The effect was in animal experiments after oral, parenteral and dermal application in those with severe parasites Test animals tested. The dosages used were tolerated very well by the experimental animals.

The active compounds according to the invention can be used as anthelmintics be used.

The active compounds according to the invention can be used together with other common anthelmintics.

The active compounds according to the invention can either be used as such or in combination with pharmaceutically acceptable Carriers are used. As dosage forms in combination with various inert substances Carriers come tablets, capsules, granules, aqueous Suspensions, injectable solutions, emulsions and Suspensions, elixirs, syrups, pastes and the like in Consider. Such carriers include solid diluents or fillers, a sterile, aqueous medium as well as various non-toxic organic solvents and the same. Of course, for one  oral tablets and tablets the like with sweetener additive and the like will. The therapeutically active compound is said to aforementioned case in a concentration of about 0.5 to 90% by weight of the total mixture is present, d. H. in Amounts that are sufficient to meet the above To achieve dosage scope.

The formulations are prepared in a known manner e.g. B. by stretching the active ingredients with solvents and / or carriers, optionally using of emulsifiers and / or dispersants, z. B. in the case of using water as a diluent optionally organic solvents as auxiliary solvents can be used.

Examples of auxiliary substances are: Water, non-toxic organic solvents such as Paraffins (e.g. petroleum fractions), vegetable oils (e.g. Peanut (sesame oil), alcohols (e.g. ethyl alcohol, glycerin), Glycols (e.g. propylene glycol, polyethylene glycol) and Water; solid carriers, such as. B. natural stone powder (e.g. kaolins, clays, talc, chalk) synthetic Rock powder (e.g. highly disperse silica, silicates), Sugar (e.g. cane, milk and dextrose); Emulsifiers, such as non-ionic and anionic emulsifiers (e.g. polyoxyethylene fatty acid esters, polyoxyethylene Fatty alcohol ethers, alkyl sulfonates and aryl sulfonates), Dispersing agents (e.g. methyl cellulose, starch and Polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, Talc, stearic acid and sodium lauryl sulfate).  

In the case of oral use, tablets can of course be taken in addition to the carriers mentioned, also additives such as sodium citrate, calcium carbonate and dicalcium phosphate, along with various additives, such as Starch, preferably potato starch, gelatin and the like, contain. Furthermore, lubricants such as Magnesium stearate, sodium lauryl sulfate and talc to Tableting can also be used.

In the case of aqueous suspensions and / or elixirs for Oral use, the active ingredients can except with the above-mentioned auxiliaries with various Flavor enhancers or colorants are added.

In the case of parenteral use, solutions can be found Dragees, ampoules, etc., also in the form of dosage units be, each dosage unit is adapted so that they are a single dose of the active ingredient delivers.

The active compounds according to the invention can be used in the formulations also in mixtures with others in the veterinary and / or human medicine for the treatment of infections and / or diseases use known active ingredients are present, in particular L-2,3,5,6-tetrahydro-6-phenyl- imidazothiazole, benzimidazole carbamates, praziquantel, Febantel.  

The active substances can be used in the usual way. The application is preferably oral, a parenteral, especially subcutaneous, but also dermal Applications (pour-on, spot-on) are possible.

In general, it has proven to be advantageous Amounts from about 1 to about 100 mg of the active ingredients per kg Body weight per day for effective results to administer.

Nevertheless, it may be necessary from the deviate quantities mentioned, depending on Body weight of the test animal or the type of application route, but also because of the animal species and their individual behavior towards the drug or the Type of its formulation and the time or interval, at which the administration takes place. So it can be in be sufficient in some cases with less than the above Minimum amount to get along while in others If the specified upper limit must be exceeded. In the case of application of larger quantities, it can be recommended be this in several single doses throughout the day to distribute. For application in veterinary medicine the same dosage range is provided. Analogous the other statements above also apply.  

Example A In vitro nematode test Caenorhabditis elegans

10 ^-4 g of active ingredient are dissolved in 1 ml of water or 0.1 ml of dimethyl sulfoxide (DMSO). This solution was placed on a replica plate. To this were added 2 ml of an E. coli suspension, to which 10-20 female animals or larvae of Caenorhabditis elegans in 0.5 ml of sterile M9 buffer solution had been added. The E. coli suspension was prepared by adding 1.8 l of sterile M9 buffer solution to 300 ml of an overnight culture of an uracil-needy E. coli strain.

The test batch was incubated at 22 ° C. for 7 days and then evaluated. The extent to which the active ingredient was assessed reproductive impairment and concentration indicated at which the multiplication is prevented. Here the following results were obtained:  

In vitro nematode test

Caenorhabditis elegans

Example B In vivo nematode test Heterakis spumora

Mice experimentally infected with Heterakis spumora are treated orally by gavage for four consecutive days 32 days after the infection. The animals are sacrificed 39 days after infection and the number of parasites is determined. The active substance concentration at which at least 95% of the parasites were killed (minimum effective dose) is given:

Example C In vivo nematode test Hymenolepis nana

Mice experimentally infected with Hymenolepis nana are treated orally by gavage for four consecutive days 10 days after infection. The animals are sacrificed 17 days after infection and the number of parasites is determined. The drug concentration at which at least 95% of the parasites were killed (minimum effective dose) is given:

Example D In vivo nematode test Strongyloides ratti

Rats experimentally infected with Strongyloides ratti are treated orally by gavage for three consecutive days 7 days after infection. The animals are sacrificed 13 days after infection and the number of parasites is determined. The drug concentration at which at least 95% of the parasites were killed (minimum effective dose) is given:

Examples a) General instructions for the preparation of the invention 5-carbamoyl substituted 1,3,2-diazaphosphorines according to method a)

0.03 mol each of the 1,3,2-diazaphosphorine and the isocyanate are presented dissolved in 120 ml of dry THF and at room temperature within 30 min. with a solution of 0.03 mol (4.56 g) "DBU" in 30 ml THF offset. The initially light brown solution darkened itself and there is a slight development of heat on so that the inside temperature by water cooling must be kept below 25 ° C. Subsequently is at room temperature until complete conversion stirred (approx. 4-5 h, DC sample!). Then the evaporated entire batch, in 100 ml of methylene chloride added and with 100 ml of dilute hydrochloric acid (10%) stirred. The organic phase is separated off, with aqueous sodium bicarbonate solution washed neutral and dried over sodium sulfate. After removing the solvent on a rotary evaporator the residue is made from ligroin or isopropanol recrystallized or chromatographed.

The active ingredients of the following examples are analogous receive:  

Table 2

Claims (5)

1. Use of diazaphosphorines of the formula I in which
R ^{1 represents} aryloxy or arylthio,
R ^{2 represents} hydrogen, alkyl, aryl or aralkyl,
R ^{3 represents} hydrogen, alkyl, aryl or aralkyl,
R ^{4 represents} the rest of the formula, in which
X ^{1 represents} O or S,
R ^{5 represents} hydrogen or alkyl,
R ^{6 represents} optionally substituted phenyl.
to fight endoparasites in veterinary medicine. 2. Agents for controlling endoparasites, labeled by containing at least one diazaphosphorine of formula I according to claim 1. 3. Use of diazaphosphorines of the formula I according to Claim 1 for controlling endoparasites. 4. Process for the preparation of endoparaticides Agents, characterized in that diazaphosphorines of formula I according to claim 1 used. 5. Use of diazaphosphorines of the formula I in which
R ^{1 represents} aryloxy or arylthio,
R ^{2 represents} hydrogen, alkyl, aryl or aralkyl,
R ^{3 represents} hydrogen, alkyl, aryl or aralkyl,
R ^{4 represents} the rest of the formula, in which
X ^{1 represents} O or S,
R ^{5 represents} hydrogen or alkyl,
R ^{6 represents} optionally substituted phenyl,
for the production of endoparaticidal agents.